Longitudinal studies on the morbidity caused by malaria have been undertaken in rural communities in preparation for vaccine trials. Recent work has emphasized that variable morbidity may be associated with molecular strain variation in Plasmodium falciparum and infection with multiple strains. The biological and immunological mechanisms involved in the interaction between species and strains have been investigated over many years, with contributions from many members of staff and collaborating colleagues. Studies on plasmodial genetics, of gradually increasing complexity, and studies of reproductive strategies in Plasmodium have been carried out, notably in the Madang area. Since malaria is transmitted by anopheline mosquitoes, detailed entomological investigations in the ecosystem of the study area form an essential part of the research program.

More specific studies of the vectors include work on the biology and behaviour of the members of the Anopheles punctulatus complex, with an emphasis on the importance of sibling species, in the highlands as well as on the coast and lowlands. Sympatric and allopatric species, many of them morphologically indistinguishable, are now defined by genetic techniques. Detailed spatial studies using global positioning system (GPS) technology have been carried out. Transmission-blocking immunity and the infectivity of human populations to mosquitoes have been studied, and sporozoite rates and densities for the different species of Plasmodium in the mosquitoes have been determined.

In the absence of a vaccine, a drug intervention was evaluated using the standard antimalarial drugs (chloroquine and amodiaquine) distributed by village health aides in a community-based program. This study indicated the value of village aides where health services are not readily available but, as with other levels of health care, supervision of the health worker is essential if a high level of performance is to be sustained. The now well-known intervention of using permethrin-treated bednets to reduce person-mosquito contact has been investigated by the Institute since 1983; this appears to be an effective method of controlling malaria and one which can be widely used. This method is now officially recommended for use throughout Papua New Guinea. Further studies on insecticide-treated bednets are continuing. A project to evaluate the capacity of a group of Amele village women to make, treat and sell bednets was undertaken. Another project has been designed to evaluate different insecticides and monitor their efficacy.

Genetic and epidemiological studies have shown that ovalocytosis, a red cell polymorphism which reaches a prevalence of 35% in the Madang area, protects against malaria. Of particular significance is the finding that ovalocytosis completely prevents cerebral malaria, the most fatal form of the disease. Ovalocytosis is now being studied by molecular techniques which define a 27-base-pair deletion in the gene for band 3, an important red-cell membrane protein. This polymorphism has been selected for at significant cost to the host, to the extent that homozygosity for the genetic deletion is lethal. We have also discovered that in the Madang area there is a remarkably high prevalence of -thalassaemia and a number of variants of glucose-6-phosphate dehydrogenase, two other genetic polymorphisms which protect against malaria. Because of the very high prevalence of -thalassaemia it is possible to compare the response to malaria of homozygotes for an -globin gene deletion with that of heterozygotes, and such a study has been carried out in collaboration with colleagues from Oxford. The study has confirmed the protective effect of -thalassaemia against severe malaria and also, more surprisingly, against other severe infections. In the Wosera area (where ovalocytosis does not occur) individuals who are negative for the Gerbich blood group are being investigated for protection against malaria. More detailed studies of the relationship between HLA and malaria have been initiated. Collaborative projects have advanced our knowledge of hyperreactive malarious splenomegaly (tropical splenomegaly syndrome) in Papua New Guinea and of amyloidosis, one of the complications of recurrent malaria.

Studies on malaria in pregnant women, who are at special risk from the disease, even in a holoendemic area, and in newborn babies have been carried out, with the aims of understanding how the changes in pregnancy tip the balance in favour of the parasite and of determining the best methods for preventing malaria in pregnant women. The incidence of malarial infections in young infants in the Madang area has been shown to be unusually high.

However, despite high infection rates in pregnant women and infants severe malarial morbidity in these groups is uncommon. Particular studies have examined the immune responses of pregnant women to malaria, the importance of placental infections, the effect on birthweight, the transfer of maternal immunity, and the evidence for immune responses stimulated in utero.

Clinical and immunological studies of cerebral malaria have been carried out in collaboration with colleagues in the Madang Hospital. Drug resistance in malaria has been studied in vitro and in vivo in both the Madang and Maprik areas. The results of these studies have led to recommendations for changes in the standard treatment of malaria in PNG.

In 1988 funding was provided by the United States Agency for International Development for a project to establish a field site in Papua New Guinea for malaria vaccine epidemiology and evaluation. This increased our staff in the malaria research program and provided a new research station in Maprik in East Sepik Province, a refurbished entomology laboratory in Yagaum and new equipment for malaria work. The communities taking part in the study live in the Wosera area of Maprik District. This area has since become our major field site for research on malaria. Baseline demographic, epidemiological, parasitological, immunological, entomological and genetic studies were carried out in the area, and have been regularly updated and expanded. When in 1994 USAID suddenly withdrew their funding for the project it was kept going by funds from AusAID, which is now providing long-term support for the malaria vaccine trials field site. This enables the evaluation of malaria vaccine candidates to be undertaken in populations fully defined for the necessary outcome variables relevant to malaria. The AusAID project also provides for community development and training components.

Our early work on malaria depended on the growth in culture of malarial parasites and a number of lines were successfully established in the Institute laboratories at Yagaum. Further investigations of these parasites were carried out in Australia. In particular, this collaborative work was directed towards the production of defined molecular vaccines against the blood stages of malaria. Though this has been the thrust of our collaborative malaria research program from the beginning, it took 20 years from conception to the start of the first vaccine trial. It is gratifying to report that a combination vaccine of three blood-stage malaria antigens (MSP1, MSP2 and RESA) has now been tested in adult males and children aged 5-<10 years from the Wosera and shown to be safe and immunogenic. Further stages in the evaluation of this vaccine and the first trials of an AMA1 vaccine, the second malaria vaccine in the collaborative program, are planned and will start soon.